Cognitive disorders such as Alzheimer?s Disease (AD), Fronto-Temporal Dementia and schizophrenia are a tremendous burden on our society, as patients are often unable to care for themselves, and require extensive resources for many years. These disorders will be an even greater burden as our society grows older in the next decades. Current treatments are inadequate, and research in this arena continues to focus on mouse models. However, AD, schizophrenia, and related cognitive disorders primarily afflict the highly evolved association cortices which are poorly developed in mice, while the primary sensory cortices are little affected in these disorders. What makes the association cortices so vulnerable? And why are more basic cortical areas, such as the sensory cortices, more resistant to disease? These are fascinating evolutionary questions with immediate medical relevance. The proposed research will test the hypothesis that the highly evolved primate association cortices are more vulnerable to disease because they are regulated by Ca2+-cAMP signaling pathways in a fundamentally different manner than the evolutionarily older, sensory cortices, and that dysregulation of Ca2+-cAMP signaling following genetic or environmental insults predisposes these higher circuits to dysfunction and degeneration, e.g. through hyperphosphorylation of tau. Our data have revealed that primate prefrontal association circuits contain high levels of cAMP-regulated K+ channels near their network connections that normally serve to gate inputs and provide mental flexibility. However, this process requires precise regulation, and even small insults to regulatory processes impair cognition and may increase risk for degeneration. A striking number of these proteins are genetically linked to schizophrenia, and show changes with advancing age. We hypothesize that primate cortical circuits will have differing sensitivities to Ca2+-cAMP signaling based on their evolutionary status, with highly evolved association cortices being most responsive to Ca2+- and cAMP-K+ actions, and primary sensory cortex being least responsive. The research will use two complementary methods: 1) Multiple label, immunoelectron microscopy (immunoEM) to reveal the constellations of interacting Ca2+-cAMP-related proteins near cortical-cortical synapses, with focus on proteins linked to disease; and 2) Physiological recordings coupled with iontophoretic application of drugs to observe physiological interactions and responsiveness to elevated Ca2+-cAMP signaling. Finally, we will compare young adult vs. aged cortices to see if there is evidence of Ca2+-cAMP dysregulation and abnormal tau phoshorylation in the aged association cortex, but not in the aged sensory cortex. Our preliminary data show loss of Ca2+- cAMP regulatory proteins near synapses with advancing age, leading to increased cAMP-PKA signaling and hyperphosphorylation of tau in the aged association cortex, but not in the aged sensory cortex. The proposed research will transform our view of cognitive disorders, revealing key vulnerabilities in association cortex and providing informed therapeutic targets for prevention and/or treatment of these crippling, complex diseases.